Antagonistic action of a 25-carboxylic ester analogue of 1α,25-dihydroxyvitamin D3 is mediated by a lack of ligand-induced vitamin D receptor interaction with coactivators
Antagonistic action of a 25-carboxylic ester analogue of 1α,25-dihydroxyvitamin D3 is mediated by a lack of ligand-induced vitamin D receptor interaction with coactivators
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DOI：
10.1074/jbc.m910000199
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发表时间：
2000-06-02
影响因子：
4.8
通讯作者：
Carlberg, C
中科院分区：
文献类型：
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作者：
Herdick, M;Steinmeyer, A;Carlberg, C
1 α，25-二羟基维生素D-3（1 α，25-（OH）（2）D-3）的25-羧酸酯类似物ZK 159222被描述为1 α，25-（OH）（2）D-3信号传导的新型拮抗剂。ZK 159222促进1 α，25-（OH）（2）D-3受体（VDR）和1 α，25-（OH）（2）D-3反应元件（VDRE）上类维生素A X受体（RXR）之间形成复合物的配体敏感性，与1 α，25-（OH）（2）D-3相比约低7倍。然而，ZK 159222不能促进VDR与辅激活蛋白SRC-1、TIF 2和RACE的配体依赖性相互作用，无论是在溶液中还是在与DNA上的RXR的复合物中。在HeLa和COS-7细胞中的功能分析表明，ZR 159222的配体敏感性比1 α，25-（OH）（2）D-3低10-100倍，最有趣的是，与1 α，25-（OH）（2）D-3相比，其效力大幅降低。1 α，25-（OH）（2）D-3与高100倍浓度的ZK 159222共同处理，在体内和体外功能试验中均产生显著的拮抗作用。这些数据表明，ZK 159222的拮抗作用是由于缺乏配体诱导的VDR与具有平行配体敏感性的共激活剂的相互作用，这足以与天然激素竞争VDR结合。
A 25-carboxylic ester analogue of 1 alpha,25-dihydroxyvitamin D-3 (1 alpha,25-(OH)(2)D-3), ZK159222, was described as a novel type of antagonist of 1 alpha,25-(OH)(2)D-3 signaling. The ligand sensitivity of ZK159222, in facilitating complex formation between 1 alpha,25-(OH)(2)D-3 receptor (VDR) and the retinoid X receptor (RXR) on a 1 alpha,25-(OH)(2)D-3 response element (VDRE), was approximately 7-fold lower when compared with 1 alpha,25-(OH)(2)D-3. However, ZK159222 was not able to promote a ligand-dependent interaction of the VDR with the coactivator proteins SRC-1, TIF2, and RACE, neither in solution nor in a complex with RXR on DNA. Functional analysis in HeLa and COS-7 cells demonstrated a 10-100-fold lower ligand sensitivity for ZR159222 than for 1 alpha,25-(OH)(2)D-3 and, most interestingly, a potency that was drastically reduced compared with 1 alpha,25-(OH)(2)D-3. A cotreatment of 1 alpha,25-(OH)(2)D-3 with a 100-fold higher concentration of ZK159222 resulted in a prominent antagonistic effect both in functional in vivo and in in vitro assays. These data suggest that the antagonistic action of ZK159222 is due to a lack of ligand-induced interaction of the VDR with coactivators with a parallel ligand sensitivity, which is sufficient for competition with the natural hormone for VDR binding.